[unreadable] This is an application for a K24 "Mid-career Investigator Award in Patient-Oriented Research." The purpose of this application is to enable the PI to pursue an extensive research program in genetics of substance dependence with sufficient time to devote to exploration of new research directions and mentorship responsibilities. The major research projects described here are a set of multicenter affected sibling pair (ASP) linkage studies with the goal of identifying risk loci for cocaine dependence (CD) and opioid dependence (OD). The purpose of these studies is to identify, chromosomal regions containing genes predisposing to CD, OD, and nicotine dependence (ND). Completion of these projects will provide information that will, eventually, substantially increase our understanding, of the mechanisms of CD. OD, and ND, and lead to new ways to attack these pervasive societal problem therapeutically. We will collect a cumulative set of 730 families, primarily ASPs, and (whenever possible) additional siblings and parents, and complete a 10 cM genome scan using highly polymorphic STR markers and a semi-automated sequencer. Three hundred and thirty-seven families have been collected as of February 2002. Affection is defined according to DSM-IV diagnostic criteria, ascertained using the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA; based on the SSAGA) as the primary instrument. The principal method of analysis will be sibling pair linkage. This work is part of the NIDA Genetics Consortium, so at the end of the project, diagnostic data, genotypes, and DNA will be shared with other qualified investigators. CD, OD, and ND are complex genetic traits that are moderately heritable. ASP linkage with adequate sample size should therefore provide a successful pathway towards mapping the more important risk loci. We will augment this strategy by means of family controlled and case-control methods, examining candidate genes. [unreadable] [unreadable] The conduct of these studies will provide excellent opportunities for research training. This proposal would permit the PI to make a major investment in mentorship, and allow a broadening of his research program in substance dependence. [unreadable] [unreadable] [unreadable] [unreadable]